Inhibitors of post-amadori advanced glycation end products

ABSTRACT

The present invention provides compounds, pharmaceutical compositions, and methods for treating or inhibiting development of AGE- and/or ALE-associated complications in subjects in need thereof.

CROSS REFERENCE

[0001] This application claims priority to U.S. provisional patentapplication serial No. 60/407,465 filed Aug. 30, 2002, incorporated byreference herein in its entirety.

FIELD OF THE INVENTION

[0002] This application relates to the fields of chemistry, medicine,renal disease, vascular disease, hyperlipidemia, hyperglycemia, advancedglycation end-products, and advanced lipoxidation end-products.

BACKGROUND OF THE INVENTION

[0003] Advanced glycation end-products (AGEs) are carbohydrate-derivedchemical modifications and crosslinks that accumulate in long-livedtissue proteins during normal aging. The increased rate of accumulationof AGEs during hyperglycemia is implicated in the development oflong-term complications of diabetes, including but not limited toretinopathy, nephropathy, neuropathy, atherosclerosis, andcardiovascular disease. In addition, AGE formation has been implicatedin a number of other pathologies, such as normal aging processes,arthritis, connective tissue disease, amyloidoses, and neurodegenerativeamyloid diseases, such as Alzheimer's.

[0004] Advanced lipoxidation end products (ALEs) are lipid-derivedchemical modifications and crosslinks that also accumulate in long-livedtissue proteins during normal aging, and are associated withhyperlipidemia, vascular disease, and renal disease in both diabetic andnon-diabetic animal models. It is now recognized that some compounds,such as N^(ε)-(carboxymethyl)lysine (CML) and N^(ε)-(carboxyethyl)lysine(CEL), may be derived from either carbohydrates or lipids, leading totheir designation as AGE/ALEs. Other compounds, such as pentosidine,appear to be true AGEs, while other compounds, such asmalondialdehyde-lysine (MDA-Lys) and hydroxynonenal-lysine (HNE-Lys),are acknowledged to be ALEs, derived exclusively from lipids.

[0005] The elucidation of the pathogenic mechanisms of AGE andALE-associated complications associated with hyperglycemia and/orhyperlipidemia is critical for developing rational therapy for theirtreatment and prevention. However, there is no consensus at present onthe relative importance of the different possible pathogenic mechanismsthat potentially contribute to these diabetic complications.

[0006] The compound pyridoxamine has recently been shown to inhibit bothAGE and ALE formation in vitro, and to be useful for treating andpreventing AGE and ALE-associated complications in hyperglycemic,hyperlipidemic, and hyperglycemic-hyperlipidemic animal models. (See,for example, U.S. Pat. No. 5,985,857; WO 00/21516; WO 00/23063) Suchcomplications include, but are not limited to, diabetic nephropathy,proteinuria, impaired glomerular clearance, retinopathy, neuropathy,atherosclerosis, diabetes-associated hyperlipidemia, oxidativemodification of proteins, urinary stone disease, obesity-relatedcomplications, proliferation or smooth muscle cells in the aorta,coronary artery occlusion, and hypertension; and dialysis-relateddisorders including dialysis-related cardiac morbidity and mortality,dialysis-related amyloidosis, dialysis-related increases in permeabilityof the peritoneal membrane in a dialysis patient, renal failureprogression in a dialysis patient, and inhibiting ultrafiltrationfailure and peritoneal membrane destruction in a dialysis patient.

[0007] However, there remains a need in the art for further options totreat or inhibit development of AGE- and ALE-associated complications inpatients in need thereof, particularly patients with hyperglycemiaand/or hyperlipidemia.

SUMMARY OF THE INVENTION

[0008] The present invention provides compounds, pharmaceuticalcompositions, and methods for treating or inhibiting development of AGE-and/or ALE-associated complications in a subject in need thereof. Thus,the invention provides novel compounds, detailed below, andpharmaceutical compositions thereof. In a preferred embodiment, themethods comprise administering one or more of the compounds orpharmaceutical compositions of the invention to subjects suffering fromhyperglycemia and/or hyperlipidemia. The invention further comprisesmethods of treating or inhibiting development of disorders includingdiabetic nephropathy, proteinuria, impaired glomerular clearance,retinopathy, neuropathy, atherosclerosis, diabetes-associatedhyperlipidemia, oxidative modification of proteins, arthritis,connective tissue diseases, amyloidosis, urinary stone disease,obesity-related complications, proliferation of smooth muscle cells inthe aorta, coronary artery occlusion, and hypertension; anddialysis-related disorders including dialysis-related cardiac morbidityand mortality, dialysis-related amyloidosis, dialysis-related increasesin permeability of the peritoneal membrane in a dialysis patient, renalfailure progression in a dialysis patient, and inhibitingultrafiltration failure and peritoneal membrane destruction in adialysis patient. Said methods comprise administering an effectiveamount of one or more compounds of the present invention, or apharmaceutically acceptable salt thereof, to a subject in need of suchtreatment.

BRIEF DESCRIPTION OF THE FIGURES

[0009]FIG. 1 presents a synthetic scheme for [2,4′]Bipyridinyl-3′-ol(BST4944).

[0010]FIG. 2 presents a synthetic scheme for5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol (BST4997).

[0011]FIG. 3 presents a synthetic scheme for3-Hydroxy-pyridine-4-carbaldehyde itermediate.

[0012]FIG. 4 presents a method for protecting the 3-OH during synthesisof 3-Hydroxy-pyridine-4-carbaldehyde intermediate.

[0013]FIG. 5 presents a synthetic scheme for4-(1H-Imidazol-2-yl)-pyridin-3-ol (BST4996) from3-Hydroxy-pyridine-4-carbaldehyde.

[0014]FIG. 6 presents synthetic schemes to produce other derivativesaccording to the invention. PG, PG1, and G2P refer to suitableprotecting groups; LG refers to a suitable leaving group. (A) Productionof 2′-halogen, 2′-secondary alcohol, and 2′-keto derivatives; (B)Production of 2′-alkenyl derivatives; (C) Production of 2′-hydroxymethyland 2′-alkoxyalkyl derivatives (D) Production of 2′-methylaminederivatives; (E) Production of 3′-alkoxyalkyl and 3′-alkoxyl-5′-ketoderivatives; (F) Production of 5′-keto-2′methylhalogen derivatives; (G)Production of 5′-alkyl derivatives.

[0015]FIG. 7 details one method for modifying the hydroxymethyl group ofBST-4997 to produce derivatives thereof.

[0016]FIG. 8 details two methods for acylating the nitrogen atom in theimidazole ring of BST-4997 to provide various derivatives thereof.

[0017]FIG. 9 details a method for alkylating the nitrogen atom in theimidazole ring of BST-4997 by amino acid alkyl halides to providevarious derivatives thereof.

[0018]FIG. 10 details one method for making mono- and di-substitutedpyrimidine derivatives.

[0019]FIG. 11 details a method for making tri-substituted pyrimidinederivatives.

[0020]FIG. 12 details two methods for making substituted imidazolederivatives.

[0021]FIG. 13 is a graphical representation of the effect of BST-4997 onrestoring nerve conduction velocity in streptozotocin diabetic rats.

[0022]FIG. 14 is a graphical representation of the effect of BST-4997 onrestoring endoneurial perfusion in streptozotocin diabetic rats.

[0023]FIG. 15 is a graphical representation of the effect of BST-4997 onimproving pain related measures in streptozotocin diabetic rats.

DETAILED DESCRIPTION OF THE INVENTION

[0024] In one aspect, the invention is directed to compounds of FormulaI:

[0025] or pharmaceutically acceptable salts thereof, wherein

[0026] L is N,N⁺O⁻, or N⁺-Z with any counterion, wherein Z is C₁-C₆alkyl;

[0027] A is a bond, C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkyl-O—, C₁-C₄alkoxy C₁-C₄ alkyl-, —N(R₂₀)C₁-C₄ alkyl, —C₁-C₄ alkyl-N(R₂₀)—, —C₁-C₂alkyl-N(R₂₀)—C₁-C₂ alkyl, —S—C₁-C₄ alkyl, —C₁-C₄ alkyl-S—, or C₁-C₄thioalkoxy C₁-C₄ alkyl-, wherein

[0028] R₂₀ is H or C₁-C₄ alkyl;

[0029] R₈ is H, —CH₂OR₂ or OR₂;

[0030] R₉ is —CH₂OR₁ or OR₁;

[0031] R₁ and R₂ are independently H, C₁-C₆ alkyl, C₁-C₆ alkanoyl,C(O)NR₃R₄, C₁-C₆ alkoxy C₁-C₆ alkyl, arylalkyl or arylalkanoyl, wherein

[0032] the alkyl, alkanoyl and alkoxy groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄alkoxy or NH₂; R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,arylalkyl, arylalkanoyl, or —CO₂alkyl, —CO₂alkylaryl; wherein

[0033] the aryl portion of each arylalkyl or each arylalkanoyl isunsubstituted or substituted with 1, 2, 3, 4, 5 groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl,haloalkoxy, or nitro;

[0034] n is 0, 1, 2, or 3;

[0035] R₇ and R₁₀ are independently H, C₁-C₆ alkyl or C₂-C₈ alkenyl,each of which is unsubstituted or substituted by 1 or 2 groups that areindependently hydroxy, halogen, NR₃R₄, alkoxy, heteroarylalkoxy,heterocycloalkylalkoxy, arylalkoxy, or aryl; wherein 1 or 2 carbons ofthe alkyl or alkenyl group can be replaced with a C(O) group or a CHOgroup;

[0036] Z is heterocycloalkyl or heteroaryl, which is unsubstituted orsubstituted with 1, 2, 3, or 4 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, aryl C₁-C₆ alkanoyl,aryl C₁-C₆ alkoxy, C₁-C₆ alkanoyl, hydroxy, hydroxy C₁-C₆ alkyl, NR₃R₄,or —C₁-C₆ alkyl NR₃R₄, wherein R₃ and R₄ are independently H, C₁-C₆alkyl, C₁-C₆ alkoxy, arylalkyl, arylalkanoyl, or —CO₂alkyl,—CO₂alkylaryl;

[0037] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy orhalogen,

[0038] the aryl, heteroaryl, and heterocycloalkyl groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro;

[0039] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above;

[0040] provided that the Z group is attached to the CH₂ group or thepyridine ring through a carbon-carbon bond;

[0041] provided that when Z is tetrahydropyridine or piperidine, the Zgroup is attached via a carbon that is adjacent to a nitrogen atom.

[0042] As used herein, a “counterion” is a negatively charged ion, suchas chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate,nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzenesulfonate, and the like.

[0043] As used herein, the term “alkenyl” refers to a straight orbranched hydrocarbon of a designed number of carbon atoms containing atleast one carbon-carbon double bond. Examples of “alkenyl” includevinyl, allyl, and 2-methyl-3-heptene.

[0044] The term “alkoxy” represents an alkyl group of indicated numberof carbon atoms attached to the parent molecular moiety through anoxygen bridge. Examples of alkoxy groups include, for example, methoxy,ethoxy, propoxy and isopropoxy.

[0045] As used herein, the term “alkyl” includes straight or branchedsaturated hydrocarbons. C₁-C₆ alkyl refers to a straight or branchedsaturated hydrocarbon containing 1, 2, 3, 4, 5, or 6 carbon atoms.Examples of “alkyl” groups include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like. Subgroups, such as, for example C₁-C₄ alkyl or C₃-C₅ arealso contained within the above definition.

[0046] The term “alkanoyl” refers to a straight or branched alkyl groupattached to the parent molecular moiety through a —C(O)— group. Examplesof alkanoyl groups include, but are not limited to, acetyl andpropionyl. A C₁-C₆ alkanoyl group is comprised of a C₁-C₆ alkyl groupattached to the parent molecular moiety through a —C(O)— group. The term“arylalkanoyl” refers to an aryl group that is attached to the parentmolecular moiety through an alkanoyl group. Examples of alkanoyl groupsinclude, but are not limited to phenylacetyl, and phenylpropionyl. Theterm “aryl” refers to an aromatic hydrocarbon ring system containing atleast one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examplesof aryl groups include phenyl and naphthyl. Preferred aryl groups have6, 7, 8, 9, or 10 carbon atoms in the ring system.

[0047] The terms “halogen” or “halo” indicate fluorine, chlorine,bromine, and iodine.

[0048] The term “heterocycloalkyl,” refers to a non-aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heterocycloalkyl ring may be optionally fused to orotherwise attached to other heterocycloalkyl rings and/or non-aromatichydrocarbon rings. Preferred heterocycloalkyl groups have from 3, 4, 5,6, or 7 members. Examples of heterocycloalkyl groups include, forexample, piperazine, morpholine, piperidine, tetrahydrofuran,pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups includepiperidinyl, piperazinyl, morpholinyl, and pyrolidinyl.

[0049] The term “heteroaryl” refers to an aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heteroaryl ring may be fused or otherwise attached to one ormore heteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

[0050] The term “heterocycloalkylalkoxy” refers to a heterocycloalkylgroup attached to the parent molecular moiety through an alkoxy group.

[0051] The term “heteroarylalkoxy” refers to a heteroaryl group attachedto the parent molecular moiety through an alkoxy group.

[0052] Non-toxic pharmaceutically acceptable salts include, but are notlimited to salts of inorganic acids such as hydrochloric, sulfuric,phosphoric, diphosphoric, hydrobromic, and nitric or salts of organicacids such as formic, citric, malic, maleic, fumaric, tartaric,succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic,2-hydroxyethylsulfonic, salicylic and stearic. Similarly,pharmaceutically acceptable cations include, but are not limited tosodium, potassium, calcium, aluminum, lithium and ammonium. Thoseskilled in the art will recognize a wide variety of non-toxicpharmaceutically acceptable addition salts.

[0053] The present invention also encompasses the acylated prodrugs ofthe compounds disclosed herein Those skilled in the art will recognizevarious synthetic methodologies, which may be employed to preparenon-toxic pharmaceutically acceptable addition salts and acylatedprodrugs of the compounds of the present invention.

[0054] The compounds of this invention may contain one or moreasymmetric carbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatographyusing, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound.

[0055] When the compounds described herein contain olefinic double bondsor other centers of geometric asymmetry, and unless otherwise specified,it is intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

[0056] The present invention also encompasses the prodrugs of thecompounds disclosed herein. Those skilled in the art will recognizevarious synthetic methodologies that may be employed to preparenon-toxic pharmaceutically acceptable prodrugs of the compoundsdisclosed herein. Those skilled in the art will recognize a wide varietyof non-toxic pharmaceutically acceptable solvates, such as water,ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.

[0057] In a second embodiment of general formula I, the Z group containsat least one nitrogen atom.

[0058] In a third embodiment of general formula I,

[0059] A is C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkyl-O—, C₁-C₄ alkoxyC₁-C₄ alkyl-, —N(R₂₀)C₁-C₄ alkyl, —C₁-C₄ alkyl-N(R₂₀)—, —C₁-C₂alkyl-N(R₂₀)—C₁-C₂ alkyl, —S—C₁-C₄ alkyl, —C₁-C₄ alkyl-S—, or C₁-C₄thioalkoxy C₁-C₄ alkyl-, wherein

[0060] R₂₀ is H or C₁-C₄ alkyl;

[0061] R₇ and R₁₀ are independently H, C₁-C₆ alkyl or C₂-C₈ alkenyl,each of which is unsubstituted or substituted by 1 or 2 groups that areindependently hydroxy, NR₃R₄, heteroarylalkoxy, heterocycloalkylalkoxy,arylalkoxy, or aryl; wherein 1 or 2 carbons of the alkyl or alkenylgroup can be replaced with a C(O) group or a CHO group; and

[0062] Z is quinazoline; quinoxaline; imidazole; benzimidazole;piperazine; morpholine; thiomorpholine; quinoline; isoquinoline; 3-, 4-,5-, 6-, 7-, or 8-tetrahydroisoquinoline; 1,2,4-triazole;hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrrole;pyrimidine; pyrazine; isothiazole; 4(3H)-pyrimidinone; isoxazole;1,3,5-triazine; hexahydropyrimidine; furan; tetrahydrofuran;tetrahydropyrimidine; piperidine; tetrahydropyridine; indole; indoline;benzoxazole; 1H-1,2,3-triazole; azocine; or imidazolidine; each of whichis unsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, arylC₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, C₁-C₆ alkanoyl, hydroxy, hydroxyC₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl NR₃R₄, wherein R₃ and R₄ at eachoccurrence areas defined above and

[0063] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy orhalogen,

[0064] the aryl groups are unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen,haloalkyl, haloalkoxy, or nitro,

[0065] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above;

[0066] provided that the Z group is attached to the CH₂ group through acarbon-carbon bond;

[0067] provided that when Z is tetrahydropyridine or piperidine, the Zgroup is attached via a carbon that is adjacent to a nitrogen atom.

[0068] In a fourth embodiment, which is a preferred version of the thirdembodiment,

[0069] A is C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkyl-O—, C₁-C₄ alkoxyC₁-C₄ alkyl-, —NR₂₀)C₁-C₄ alkyl, —C₁-C₄ alkyl-N(R₂₀)—, —C₁-C₂alkyl-N(R₂₀)—C₁-C₂ alkyl, —S—C₁-C₄ alkyl, —C₁-C₄ alkyl-S—, or C₁-C₄thioalkoxy C₁-C₄ alkyl-, wherein

[0070] R₂₀ is H or C₁-C₄ alkyl; and Z contains at least two nitrogenatoms.

[0071] In a fifth embodiment, which is a preferred version of the fourthembodiment,

[0072] R₇ and R₁₀ are independently H, C₁-C₆ alkyl, which isunsubstituted or substituted by 1 or 2 groups that are independentlyhydroxy, NR₃R₄, heteroarylalkoxy, heterocycloalkylalkoxy, arylalkoxy, oraryl; and

[0073] Z is quinazoline; quinoxaline; imidazole; benzimidazole;piperazine; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine;pyrazole; pyrimidine; pyrazine; 4(3H)-pyrimidinone; 1,3,5-triazine;hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine; indole;indoline; 1H-1,2,3-triazole; or imidazolidine, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, arylC₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, alkanoyl, hydroxy C₁-C₆ alkyl, NR₃R₄,or —C₁-C₆ alkyl-NR₃R₄, wherein

[0074] R₃ and R₄ at each occurrence are independently H, C₁-C₆ alkyl,C₁-C₆ alkoxy, arylalkyl, arylalkanoyl, C₁-C₆ alkanoyl, —CO₂alkyl,—CO₂alkylaryl

[0075] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy orhalogen,

[0076] the aryl groups are unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen,haloalkyl, haloalkoxy, or nitro,

[0077] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above;

[0078] provided that the Z group is attached to the CH₂ group or thepyridine ring through a carbon-carbon bond;

[0079] provided that when Z is tetrahydropyridine or piperidine, the Zgroup is attached via a carbon that is adjacent to a nitrogen atom.

[0080] In a sixth embodiment, which is a preferred version of the fifthembodiment

[0081] R₇ and R₁₀ are independently H, C₁-C₆ alkyl which isunsubstituted or substituted by 1 or 2 groups that are independentlyhydroxy, or NR₃R₄; wherein 1 or 2 carbons of the alkyl or alkenyl groupcan be replaced with a C(O) group or a CHO group; and Z is imidazole;benzimidazole; piperazine; 1,2,4-triazole; hexahydropyridazine;tetrahydropyridazine; pyrazole; pyrimidine; pyrazine;hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine; indole;indoline; 1H-1,2,3-triazole; or imidazolidine, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenylC₁-C₆ alkanoyl, phenyl C₁-C₆ alkoxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or—C₁-C₆ alkyl-NR₃R₄, wherein

[0082] R₃ and R₄ are independently H, C₁-C₆ alkyl, benzyl, benzoyl,C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂alkylphenyl;

[0083] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy,fluoro, or chloro;

[0084] the phenyl groups are unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, fluoro,chloro, CF₃, OCF₃, or nitro;

[0085] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above;

[0086] provided that the Z group is attached to the CH₂ group through acarbon-carbon bond;

[0087] provided that when Z is tetrahydropyridine or piperidine, the Zgroup is attached via a carbon that is adjacent to a nitrogen atom.

[0088] In a seventh embodiment, which is a preferred version of thethird embodiment, R₁ and R₂ are independently H, C₁-C₆ alkoxy C₁-C₆alkyl, arylalkyl or arylalkanoyl, wherein

[0089] the aryl portion of each arylalkyl or each arylalkanoyl isunsubstituted or substituted with 1, 2, 3, 4, 5 groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl,haloalkoxy, or nitro; and

[0090] the alkyl, alkanoyl and alkoxy groups are independentlysubstituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄alkoxy or NH₂.

[0091] In an eight embodiment, which is a preferred version of the sixthembodiment, R₁ and R₂ are independently hydrogen, C₁-C₄ alkyl, orbenzyl, wherein

[0092] the phenyl portion of each benzyl is unsubstituted or substitutedwith 1, 2, or 3, groups that are independently C₁-C₄ alkyl, C₁-C₄alkoxy, hydroxy, fluoro, chloro, CF₃, OCF₃, or nitro; and

[0093] the alkyl groups are independently substituted with 1, or 2,groups that are independently hydroxy, methoxy, ethoxy, propoxy,isopropoxy or NH₂.

[0094] In a ninth embodiment, which is a preferred version of the fourthembodiment,

[0095] R₇ and R₁₀ are independently H, C₁-C₆ alkyl, which isunsubstituted or substituted by 1 or 2 groups that are independentlyhydroxy, or NR₃R₄, heteroarylalkoxy, heterocycloalkylalkoxy, arylalkoxy,or aryl;

[0096] the aryl, heteroaryl, or heterocycloalkyl groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro,

[0097] A tenth embodiment, which is a preferred version of generalformula I, is a compound of the formula:

[0098] In an eleventh embodiment, which is a preferred version of thetenth embodiment, the Z group contains at least one nitrogen atom.

[0099] In a twelfth embodiment, which is a preferred version of theeleventh embodiment,

[0100] Z is quinazoline; quinoxaline; imidazole; benzimidazole;piperazine; morpholine; thiomorpholine; quinoline; isoquinoline; 3, 4,5, 6, 7, or 8-tetrahydroisoquinoline; 1,2,4-triazole;hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrimidine;pyrazine; isothiazole; 4(3H)-pyrimidinone; isoxazole; 1,3,5-triazine;hexahydropyrimidine; furan; tetrahydrofuran; tetrahydropyrimidine;piperidine; tetrahydropyridine; indole; indoline, benzoxazole;1H-1,2,3-triazole; azocine; or imidazolidine; each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxy C₁-C₆ alkoxy, halo C₁-C₆ alkyl, halo C₁-C₆ alkyl, aryl C₁-C₆alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, alkanoyl, hydroxy C₁-C₆alkyl, NR₃R₄, or —C₁-C₆alkyl NR₃R₄, wherein

[0101] R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,arylalkyl, arylalkanoyl, C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂alkylaryl;

[0102] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy orhalogen,

[0103] the aryl groups are unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen,haloalkyl, haloalkoxy, or nitro,

[0104] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above;

[0105] provided that the Z group is attached to the pyridine ringthrough a carbon-carbon bond;

[0106] provided that when Z is tetrahydropyridine or piperidine, the Zgroup is attached via a carbon that is adjacent to a nitrogen atom;

[0107] provided that when Z is hexahydropyrimidine, it is substitutedwith two or three groups.

[0108] In a thirteenth embodiment, which is a preferred version of thetwelfth embodiment, Z contains at least two nitrogen atoms.

[0109] In a fourteenth embodiment, which is a preferred version of thethirteenth embodiment

[0110] Z is quinazoline; quinoxaline; imidazole; benzimidazole;piperazine; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine;pyrazole; pyrimidine; pyrazine; 4(3H)-pyrimidinone; 1,3,5-triazine;hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine; indole;indoline; 1H-1,2,3-triazole; or imidazolidine, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, arylC₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, alkanoyl, hydroxy C₁-C₆ alkyl, NR₃R₄,or —C₁-C₆ alkyl-NR₃R₄, wherein

[0111] R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,arylalkyl, arylalkanoyl, C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂alkylaryl

[0112] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy orhalogen,

[0113] the aryl groups are unsubstituted or substituted with 1, 2, 3, 4,or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen,haloalkyl, haloalkoxy, or nitro,

[0114] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above;

[0115] provided that the Z group is attached to the pyridine ringthrough a carbon-carbon bond;

[0116] provided that when Z is hexahydropyrimidine, it is substitutedwith two or three groups.

[0117] In a fifteenth embodiment, which is a preferred version of thefourteenth embodiment,

[0118] Z is imidazole; benzimidazole; piperazine; 1,2,4-triazole;hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrimidine;pyrazine; hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine;indole; indoline; 1H-1,2,3-triazole; or imidazolidine, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenylC₁-C₆ alkanoyl, phenyl C₁-C₆ alkoxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or—C₁-C₆ alkyl-NR₃R₄, wherein

[0119] R₃ and R₄ are independently H, C₁-C₆ alkyl, benzyl, benzoyl,C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂alkylphenyl;

[0120] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy,fluoro, or chloro;

[0121] the phenyl groups are unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, fluoro,chloro, CF₃, OCF₃, or nitro;

[0122] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above;

[0123] provided that the Z group is attached to the pyridine ringthrough a carbon-carbon bond;

[0124] provided that when Z is hexahydropyrimidine, it is substitutedwith two or three groups.

[0125] In a sixteenth embodiment, which is a preferred version of thefifteenth embodiment,

[0126] R₁ and R₂ are independently H, C₁-C₆ alkoxy C₁-C₆ alkyl,arylalkyl or arylalkanoyl, wherein

[0127] the aryl portion of each arylalkyl or each arylalkanoyl isunsubstituted or substituted with 1, 2, 3, 4, 5 groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl,haloalkoxy, or nitro; and

[0128] the alkyl, alkanoyl and alkoxy groups are independentlysubstituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄alkoxy or NH₂.

[0129] In a seventeenth embodiment, which is a preferred version of thesixteenth embodiment,

[0130] R₁ and R₂ are independently hydrogen, C₁-C₄ alkyl, or benzyl,wherein

[0131] the phenyl portion of each benzyl is unsubstituted or substitutedwith 1, 2, or 3, groups that are independently C₁-C₄ alkyl, C₁-C₄alkoxy, hydroxy, fluoro, chloro, CF₃, OCF₃, or nitro; and

[0132] the alkyl groups are independently substituted with 1, or 2,groups that are independently hydroxy, methoxy, ethoxy, propoxy,isopropoxy or NH₂.

[0133] In an eighteenth embodiment, which is a further embodiment of thefirst embodiment, the compounds of the invention are directed tocompounds of the formula:

[0134] or pharmaceutically acceptable salts thereof, wherein

[0135] R₈ is H, —CH₂OR₂ or OR₂;

[0136] R₁ and R₂ are independently H, C₁-C₆ alkyl, C₁-C₆ alkanoyl, C₁-C₆alkoxy C₁-C₆ alkyl, arylalkyl or arylalkanoyl, wherein

[0137] the alkyl, alkanoyl and alkoxy groups are unsubstituted orsubstituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄alkoxy or NH₂;

[0138] R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy,arylalkyl, arylalkanoyl, or —CO₂alkyl, —CO₂ alkylaryl; wherein

[0139] the aryl portion of each arylalkyl or each arylalkanoyl isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl,haloalkoxy, or nitro;

[0140] R₇ and R₁₀ are independently H, C₁-C₆ alkyl or C₂-C₈ alkenyl,each of which is unsubstituted or substituted by 1 or 2 groups that areindependently hydroxy, halogen, NR₃R₄, alkoxy, heteroarylalkoxy,heterocycloalkylalkoxy, arylalkoxy, or aryl; wherein 1 or 2 carbons ofthe alkyl or alkenyl group can be replaced with a C(O) group or a CHOgroup;

[0141] Z is heterocycloalkyl or heteroaryl containing 1, 2, or 3nitrogen atoms, which is unsubstituted or substituted with 1, 2, 3, or 4groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxyC₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, arylC₁-C₆ alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, C₁-C₆ alkanoyl,hydroxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl NR₃R₄, wherein R₃and R₄ are as defined above;

[0142] each alkyl, alkoxy, and alkanoyl group is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently hydroxy orhalogen,

[0143] the aryl, heteroaryl, and heterocycloalkyl groups areunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro;

[0144] any NH group in a heterocycloalkyl or heteroaryl group canoptionally be NR₃, where R₃ is defined above.

[0145] In a preferred embodiment of the eighteenth embodiment, Z isheteroaryl. In an even more preferred embodiment of the eighteenthembodiment, the heteroaryl is selected from the group consisting ofpyridine, imidazole, diazole, and triazole, wherein said heteroaryl isunsubstituted or substituted as described for the eighteenth embodiment.

[0146] In a further preferred embodiment of the eighteenth embodiment,the Z group is attached to the pyridine ring through a carbon-carbonbond.

[0147] In a further preferred embodiment of the eighteenth embodiment, Zcontains 2 nitrogen atoms and is substituted as described for theeighteenth embodiment. In an even more preferred embodiment, Z containsan unsubstituted nitrogen atom on both sides of the attachment point ofZ.

[0148] In another preferred embodiment of the eighteenth embodiment, thearyl substituents on Z are phenyl or phenyl derivatives.

[0149] In a preferred embodiment of all of the various embodiments ofthe compounds of the invention, the L group is N. In a further preferredembodiment of all of the various embodiments of the compounds of theinvention, R₉ is OR₁.

[0150] Specific compounds according to these various embodiments include[2,4′]Bipyridinyl-3′-ol, 4-(1H-Imidazol-2-yl)-pyridin-3-ol,5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol, and othercompounds as discussed below.

[0151] In a further aspect, the present invention providespharmaceutical compositions comprising one or more compounds of theinvention, as disclosed above and a pharmaceutically acceptable carrier.Preferred embodiments of the pharmaceutical compositions are describedbelow.

[0152] In a further aspect, the present invention provides methods fortreating or inhibiting development of one or more AGE- and/orALE-associated complications in subject in need thereof comprisingadministering one or more compounds or pharmaceutical compositions ofthe invention to a subject in need thereof. As used herein, the phrase“AGE and/or ALE associated complications” includes, but is not limitedto accelerated protein aging, retinopathy, nephropathy, proteinuria,impaired glomerular clearance, neuropathy, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, atherosclerosis,cardiovascular disease, and neurodegenerative amyloid diseases, such asAlzheimer's disease, diabetes-associated hyperlipidemia, oxidativemodification of proteins, arthritis, connective tissue diseases,amyloidosis, urinary stone disease, obesity-related complicationsproliferation or smooth muscle cells in the aorta, coronary arteryocclusion, and hypertension; and dialysis-related disorders includingdialysis-related cardiac morbidity and mortality, dialysis-relatedamyloidosis, dialysis-related increases in permeability of theperitoneal membrane in a dialysis patient, renal failure progression ina dialysis patient, and inhibiting ultrafiltration failure andperitoneal membrane destruction in a dialysis patient.

[0153] In a further aspect, the invention provides methods for treatingor inhibiting development of one or more of diabetic nephropathy,proteinuria, impaired glomerular clearance, retinopathy, neuropathy,atherosclerosis, diabetes-associated hyperlipidemia, oxidativemodification of proteins, arthritis, connective tissue diseases,amyloidosis, urinary stone disease, obesity-related complicationsproliferation or smooth muscle cells in the aorta, coronary arteryocclusion, and hypertension; and dialysis-related disorders includingdialysis-related cardiac morbidity and mortality, dialysis-relatedamyloidosis, dialysis-related increases in permeability of theperitoneal membrane in a dialysis patient, renal failure progression ina dialysis patient, and inhibiting ultrafiltration failure andperitoneal membrane destruction in a dialysis patient, wherein themethods comprise administering an effective amount of one or morecompounds of the present invention, or a pharmaceutically acceptablesalt thereof, to a subject in need of such treatment. In a preferredembodiment, the methods are used to treat patients suffering fromhyperlipidemia and/or hyperglycemia or their complications, or toinhibit development of complications arising from hyperlipidemia and/orhyperglycemia, such as those described above. While the methods of thisaspect of the present invention are not limited by a specific mechanism,it is believed that the compounds of the invention are useful intreating or inhibiting development of these complications based on theirability to inhibit AGE and/or ALE formation, and thus to inhibit thedevelopment or progression of complications associated with accumulationof AGEs and/or ALEs.

[0154] As used herein, “treat” or “treating” means accomplishing one ormore of the following: (a) reducing the severity of the disorder; (b)limiting or preventing development of symptoms characteristic of thedisorder(s) being treated; (c) inhibiting worsening of symptomscharacteristic of the disorder(s) being treated; (d) limiting orpreventing recurrence of the disorder(s) in patients that havepreviously had the disorder(s); and (e) limiting or preventingrecurrence of symptoms in patients that were previously symptomatic forthe disorder(s).

[0155] As used herein, the term “inhibiting development of” means toprevent or to minimize development of the disorder or complication inindividuals at risk of developing the disorder or complication.

[0156] The instant compounds can be administered individually or incombination, usually in the form of a pharmaceutical composition. Suchcompositions are prepared in a manner well known in the pharmaceuticalart and comprise at least one active compound.

[0157] The compounds of the invention can be administered as the soleactive pharmaceutical agent, or they can be used in combination with oneor more other compounds useful for carrying out the methods of theinvention, including but not limited to pyridoxamine, aminoguanidine,and agents that promote glycemic control, such as insulin, metformin,and thiazolidinediones. When administered as a combination, thetherapeutic agents can be formulated as separate compositions that aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

[0158] The compounds may be made up in a solid form (including granules,powders or suppositories) or in a liquid form (e.g., solutions,suspensions, or emulsions). The compounds of the invention may beapplied in a variety of solutions and may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc.

[0159] The compounds of the invention may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of the invention and apharmaceutically acceptable carrier. One or more compounds of theinvention may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of the invention may be in a form suitable for oraluse, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

[0160] Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques. Insome cases such coatings may be prepared by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monosterate or glyceryl distearate maybe employed.

[0161] Formulations for oral use may also be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

[0162] Aqueous suspensions contain the active materials in admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

[0163] Oily suspensions may be formulated by suspending the activeingredients in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoringagents may be added to provide palatable oral preparations. Thesecompositions may be preserved by the addition of an anti-oxidant such asascorbic acid.

[0164] Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Suitable dispersing or wettingagents or suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

[0165] Pharmaceutical compositions of the invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oil ora mineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

[0166] Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

[0167] The compounds and pharmaceutical compositions of the presentinvention may also be administered in the form of suppositories, e.g.,for rectal administration of the drug. These compositions can beprepared by mixing the drug with a suitable non-irritating excipientthat is solid at ordinary temperatures but liquid at the rectaltemperature and will therefore melt in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycols.

[0168] Compounds and pharmaceutical compositions of the presentinvention may be administered parenterally in a sterile medium. Thedrug, depending on the vehicle and concentration used, can either besuspended or dissolved in the vehicle. Advantageously, adjuvants such aslocal anesthetics, preservatives and buffering agents can be dissolvedin the vehicle.

[0169] Dosage levels of the order of from about 0.01 mg to about 50 mgper kilogram of body weight per day, and more preferably between 0.1 mgto about 50 mg per kilogram of body weight per day, are useful in thetreatment of the above-indicated conditions. The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.

[0170] Pharmaceutical compositions containing the compounds describedherein are administered to an individual in need thereof. In a preferredembodiment, the subject is a mammal; in a more preferred embodiment, thesubject is a human. In therapeutic applications, compositions areadministered in an amount sufficient to carry out the methods of theinvention. Amounts effective for these uses depend on factors including,but not limited to, the nature of the compound (specific activity,etc.), the route of administration, the stage and severity of thedisorder, the weight and general state of health of the subject, and thejudgment of the prescribing physician. The active compounds areeffective over a wide dosage range. However, it will be understood thatthe amount of the compound actually administered will be determined by aphysician, in the light of the above relevant circumstances. Therefore,the above dosage ranges are not intended to limit the scope of theinvention in any way.

[0171] For administration to non-human mammals, the composition may alsobe added to the animal feed or drinking water. It may be convenient toformulate these animal feed and drinking water compositions so that theanimal ingests an appropriate quantity of the composition during a mealor throughout the course of the day. It may also be convenient topresent the composition as a premix for addition to the feed or drinkingwater.

[0172] The starting materials and various intermediates may be obtainedfrom commercial sources, prepared from commercially available organiccompounds, or prepared using well-known synthetic methods.

[0173] Representative examples of methods for preparing specificembodiments of the invention are set forth below.

EXAMPLE 1 Synthesis of [2,4′]Bipyridinyl-3′-ol (BST4944)

[0174] The synthetic scheme for [2,4′]Bipyridinyl-3′-ol is provided inFIG. 1. Diethyl-carbamic acid [2,4′]bipyridinyl-3′-yl ester (FW: 271,395 mg, 1.45 mmol) was refluxed for two hours in MeOH (3 ml) to whichsodium methoxide was added (800 μl). The solution was then kept for 2hours at room temperature, followed by removal of solvent. After removalof solvent, the residue was re-dissolved in EtOAc and water and thenneutralized to pH 7 with diluted H₂SO₄. Extractions with 10:1 EtOAc/MeOHwere dried over MgSO₄, filtered and concentrated to afford 292 mg ofproduct in oil.

[0175] Physical Properties

[0176] Compound C₁₀H₈N₂O, FW: 172.19

[0177] Purification Method: Extraction and Dryness

[0178] Purity: 75% TABLE 1 Spectral properties Compound pH2.0 pH7.4pH9.4 BST 4944 λ_(max1) (nm) 266 266 266 ε_(max1) (× 10⁻³) 1.54 1.521.38 λ_(max2) (nm) 273 273 273 ε_(max2) (× 10⁻³) 1.71 1.68 1.43 λ_(max3)(nm) 284 288 288 ε_(max3) (× 10⁻³) 1.84 1.46 1.14 λ_(max4) (nm) 293 317319 ε_(max4) (× 10⁻³) 1.75 1.19 1.09 λ_(max5) (nm) 322 ε_(max5) (× 10⁻³)1.34

EXAMPLE 2 Synthesis of5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol (BST4997)

[0179] The synthetic scheme for5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol is providedin FIG. 2. Pyridoxal hydrochloride (251 mg, 1.24 mmol) was dissolved inMeOH (3 mL) followed by adding glyoxal (40% in water) (1 mL) andammonium hydroxide (NH₄OH) (conc. 1 mL). The reaction solution wasstirred for 16 hours. After removal of solids by filtration, thereaction solution was rotovaped to remove MeOH and purified by flashcolumn with EtOAc/MeOH (8:1) as eluent (R_(f) 0.52), yield, 179 mg, 0.88mmol, 71%.

[0180] Physical Properties

[0181] Compound: C₁₀H₁₁N₃O₂, FW: 205.22

[0182] Purification Method: Flash Column

[0183] Purity: 99% TABLE 2 Spectral Properties Compound pH2.0 pH7.4pH9.4 BST 4997 λ_(max1) (nm) 246 251 245 ε_(max1) (× 10⁻³) 7.01 7.567.57 λ_(max2) (nm) 291-301 (flat) 305 279-285 ε_(max2) (× 10⁻³) 3.983.83 (flat) 3.64 λ_(max3) (nm) 375 364 ε_(max3) (× 10⁻³) 3.41 5.53 3514.95

EXAMPLE 3 Synthesis of Intermediate Compound3-Hydroxy-pyridine-4-carbaldehyde

[0184] The synthetic scheme for 3-Hydroxy-pyridine-4-carbaldehyde isprovided in FIG. 3. Hydration followed by Hofmann rearrangement of3,4-pyridinedicarboximide (1) gave 3-amino-isonicotinic acid (2).Diazotization followed by hydrolysis of 3-amino-isonicotinic acid (2)afforded 3-hydroxy-isonicotinic acid (3). By Fischer esterification,3-hydroxy-isonicotinic acid (3) was converted to 3-hydroxy-isonicotinicacid methyl ester (4), which was reduced to 4-hydroxymehyl-pyridin-3-ol(5) and then oxidized to 3-hydroxy-pyridine-4-carbaldehyde (6).

[0185] 3-Amino-isonicotinic acid (2): Bromine (214 g, 1.34 mol) wasslowly added into pre-cooled (5° C.) sodium hydroxide (10%, 3160 g)followed by adding 3,4-pyridinedicarboximide (195 g, 1.32 mol). Thesolution was heated to 80° C. and stirred for 1 hour. After cooling to37° C., the solution was adjusted to pH 5.5 with addition of acetic acid(AcOH) (225 mL) and slowly stirred for 16 hours at 0° C. The solid wasfiltered off, washed with water, then with methanol (MeOH). The product3-amino-isonicotinic acid (2) was dried to a light brown solid, yield,112 g, 0.814 mol, 61%.

[0186] 3-Hydroxy-isonicotinic acid (3): 3-Amino-isonicotinic acid (2)(112 g, 0.814 mol) was dissolved in deionized water (1800 mL) containingsulfuric acid (H₂SO₄) (90 mL) by warming to 52° C. and then cooled downto 8° C. (solids came back out). A solution of sodium nitrite (NaNO₂)(62.1 g) in deionized water (540 mL) was slowly added over 20 min whilemaintaining a temperature of 8-10° C. The slurry was heated to 82° C.and then cooled to 65° C. AcOH (90 mL) and ammonium hydroxide (NH₄OH)(˜150 mL) were added to adjust the pH to 4.5. The reaction mixture wasfurther cooled to 0° C. and stirred for 16 hours. The product,3-hydroxy-isonicotinic acid (3), was collected by filtration as a tansolid, yield, 105 g, 0.755 mol, 93%.

[0187] 3-Hydroxy-isonicotinic acid methyl ester (4):3-Hydroxy-isonicotinic acid (3) (104 g, 0.748 mol) was refluxed withMeOH (212 mL, 5.23 mol), H₂SO₄ (60 mL, 1.12 mol) and 1,2-dichloroethane(360 mL) for 20 hours. The reaction mixture was cooled to roomtemperature and diluted with deionized water. After removal of solid byfiltration, the aqueous layer was basified with sodium bicarbonate(NaHCO₃) and refiltered. The organic layer was removed, and the aqueouslayer was extracted with chloroform (CHCl₃) (×3). The combined organiclayers were dried over magnesium sulfate (MgSO₄), filtered andconcentrated to afford an off-white solid, yield, 90 g, 0.588 mol, 78%.

[0188] 4-Hydroxymehyl-pyridin-3-ol (5): 3-Hydroxy-isonicotinic acidmethyl ester (4) (1 g, 6.5 mmol) was dissolved in ether (20 mL,anhydrous). A suspension of lithium aluminum hydride (LAH) (248 mg) inether (20 mL) was slowly added at 0° C. The mixture was stirred at roomtemperature for 6 hours until TLC showed reaction to be complete. Ethylacetate (EtOAc) was added to quench the reaction and water was added todissolve salts. After extraction with chloroform and ethyl acetate, theproduct stayed in the aqueous phase.

[0189] 3-Hydroxy-pyridine-4-carbaldehyde (6): The mixture of4-hydroxymehyl-pyridin-3-ol (5) (1 g, 6.19 mmol) and manganese oxide(MnO₂) (7 g) with TEA (861 μL) was stirred at room temperature inchloroform (CHCl₃) (50 mL, anhydrous) for 20 hours. The resultingmaterial was filtered through a celite, washed with CHCl₃ and EtOAc,rotovaped to dryness, and re-dissolved in deionized water. Then thesolution was extracted with CHCl₃ (×2), EtOAc (×2), and EtOAc/MeOH(10:1, ×5). The combined organics were dried over MgSO₄ and followed byrotovap. 220 mg of 3-hydroxy-pyridine-4-carbaldehyde (6) was obtained(˜30% yield).

[0190] Protection of the 3-OH group is shown in FIG. 4. One of skill inthe art will recognize that this is one method among many that could beused.

EXAMPLE 4 Synthesis of 4-(1H-Imidazol-2-yl)-pyridin-3-ol (BST4996)

[0191] The synthetic scheme for 4-(1H-Imidazol-2-yl)-pyridin-3-ol isprovided in FIG. 5. Intermediate compound3-hydroxy-pyridine-4-carbaldehyde (6 from FIG. 4) (200 mg, 1.63 mmol)was dissolved in MeOH (3 mL) followed by adding glyoxal (40% in water)(1 mL) and NH₄OH (conc. 1 mL). The mixture was stirred for 16 hours withsolids formed after about 30 min. Solid was filtered off and MeOH wasremoved by rotovap. The product was purified by flash column (8:2EtOAc/MeOH with 1% NH₄OH, R_(f) 0.2) and LC, yield, 176 mg, 1.09 mmol,67% (LC purity: 100%).

[0192] Physical Properties:

[0193] Compound: C₈H₇N₃O, FW: 161.16

[0194] Purification Method: Flash Column

[0195] Purity: 99% TABLE 3 Spectral Properties Compound pH 2.0 pH 7.4 pH9.4 BST 4996 λ_(max1) (nm) 287-294 (flat) 248 240 ε_(max1) (×10⁻³) 7.788.39 9.99 λ_(max2) (nm) 323-327 (flat) 307 276 ε_(max2) (×10⁻³) 7.465.43 6.24 λ_(max3) (nm) 371 357-367 344 (flat) ε_(max3) (×10⁻³) 2.437.47 7.23

EXAMPLE 5 Production of Various Other Derivatives

[0196] FIGS. 6(A)-(E) provide non-limiting examples of synthetic schemesthat can be employed to produce other compounds of the invention. “PG”refers to “protecting groups”. The various protecting groups may be thesame or different. For example, silyl groups may be used on the oxygensand benzyl groups on the nitrogen, or all protecting groups may comprisebenzyl groups.

[0197] The dehydration/elimination reaction shown in FIG. 6(B) can beconducted using methods well known in the art.

[0198]FIG. 7 details one method for modifying the hydroxymethyl group ofBST-4997 to provide various derivatives thereof. Such modification isaccomplished by introduction of an alkyl group or of any amino acid.This reaction is carried out in one step by reaction of BST-4997 with analkyl halide (ie: the “X” is a halogen) in the presence of a base asoutlined in route A of FIG. 7. The introduction of an amino acid moietyis accomplished using standard coupling reagent such asdicyclocarbonyldiimine in presence of a catalytic amount ofdimethylaminopyridine as shown in route B of FIG. 7. These processes arecarried out according to methods known in the art.

[0199]FIG. 8 details one method for modifying the nitrogen atom in theimidazole ring of BST-4997 to provide various derivatives thereof. Suchmodification is accomplished by reaction of BST-4997 with an acylchloride derived from, for example, any amino acid, in apolar solvent.Alternatively, an oxazolidinedione derivative of any amino acid isemployed in the presence of an organic base instead of the acyl chloridein the presence of a base such as triethylamine in tetrahydrofuran,chloroform mixture at low temperature. This pathway requires only a onestep reaction using, for example, commercially available glycine-derivedoxazolidinedione. Oxazolidinediones derived from other amino acids canbe synthesized according to the one step Schöllkopf (Synthesis (1981)966-971) procedure using phosgene or trisphosgene reagent in thepresence of base depending on the necessity to protect the amino acidsubstituents prior to the ring closure reaction. Oxazolidinediones fromvarious amino acids such as arginine are described in literature (J. Am.Chem. Soc. (1971) 93:2746-2754).

[0200]FIG. 9 details another method for modifying the nitrogen atom inthe imidazole ring of BST-4997 to provide various derivatives thereof.By selection of an appropriate amino acid bearing a good leaving group,such as a halide substituent in the β-position, the corresponding aminoacid substituted imidazole is accessible using standard alkylationconditions. In a typical reaction to form amino acid-substitutedimidazole derivatives, the imidazole and halide-substituted amino acidare mixed in equal molar portions and the mixture is preferably heatedin a polar solvent such as dimethylformamide.

[0201]FIG. 10 details one method for forming pyrimidine derivativesusing beta diketones. The methods discussed in relation to FIGS. 10 and11 are based on procedures disclosed by Seko and Rosenbach (Chem. Pham.Bull. (1991) 39(3):651-657; Tetrahedron Letters (1981)22(15):1453-1454). Pyrimidine derivatives are prepared by reaction ofthe pyridoxal hydrochloric with 1,3 diketone as outlined in FIG. 10. Thereactions occurs when 1,3-diketones are treated with the pyridoxal andammonium salt in polar solvent, such as dimethylsulfoxyde (DMSO)/aceticacid (AcOH), under oxidating (O₂) conditions over several hours. Underthese conditions, pyrimidine derivatives are easily purified by columnchromatography on silica gels.

[0202]FIG. 11 details another method for forming pyrimidine derivatives.Malonamides or malonimidamides are reacted with esters or otheractivated carboxylic acid derivatives under basic conditions, asoutlined in FIG. 11 (J. Chem Soc. (1951), 2214; J. Chem. Soc. (1956),2312; J. Chem. Soc. (1943), 574). Using this method, otherfunctionalities can be introduced, such as hydrophilic substituentsincluding amino or hydroxyl groups, as shown in the figure.

[0203]FIG. 12 details two methods for forming imidazole derivatives.Method A involves the reaction of pyridoxal hydrochloride and1,2-diketones under essentially the same conditions as those describedabove for reaction with 1,3 diketones. Method B utilizes an available4-pyridoxic acid according to a reaction described by Pellicciari withimidazole compounds (Arzneim. Forsch (1980) 30:2103-2105). This approachis based on silver catalyzed decarboxylation of carboxylic acid inmethanol-water by peroxydisulfate, followed by reaction of the radicalformed with imidazoles.

[0204] Using the various methods disclosed above, either alone or incombination with further methods known to those in the art, a largevariety of compounds according to the present invention can be prepared.Other specific embodiments of the compounds of the invention include thefollowing:

EXAMPLE 6 In Vitro Method to Identify Inhibitors of Post-Amadori AGEFormation

[0205] The effect of [2,4′]Bipyridinyl-3′-ol,5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol, and4-(1H-Imidazol-2-yl)-pyridin-3-ol on post-Amadori AGE formation duringinterrupted glycation of bovine serum albumin and ribonuclease A byribose was determined in comparison to pyridoxamine. Modification withribose was done at 37° C. in 0.2 M phosphate buffer of pH 7.5 containing0.02% sodium azide. The solutions were kept in capped tubes and openedonly to remove timed aliquots that were immediately frozen for latercarrying out the various analyses. “Interrupted glycation” experimentswere carried out by first incubating protein with the ribose at 37° C.for 8 or 24 h, followed by immediate and extensive dialysis againstfrequent cold buffer changes at 4° C. The samples were then re-incubatedby quickly warming to 37° C. in the absence of external ribose. Aliquotswere taken and frozen at various intervals for later analysis. (See U.S.Pat. No. 5,985,857)

[0206] The interrupted glycation method for following post-Amadorikinetics of AGE formation allows for the rapid quantitative study of“late” stages of the glycation reaction. Importantly, this method allowsfor inhibition studies that are free of pathways of AGE formation thatarise from glycoxidative products of free sugar or Schiff base (Namikipathway). The experiments were designed to determine the half-maximalinhibitory concentration of these compounds (“IC50 values”) forinhibiting the conversion of Amadori compounds to post Amadori advancedglycation endproducts.

[0207] The IC50 values determined were as follows:

[0208] [2,4′]Bipyridinyl-3′-ol (BST4944): 2 mM

[0209] 5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol(BST4997): 0.2-0.3 mM

[0210] 4-(1H-Imidazol-2-yl)-pyridin-3-ol (BST4996): 0.2-0.3 mM

[0211] These data demonstrate that these 3 compounds were very effectiveat inhibiting the conversion of Amadori compounds to post Amadoriadvanced glycation endproducts. In comparison, pyridoxamine inhibitedthe conversion of Amadori compounds to post Amadori advanced glycationendproducts with a half-maximal inhibitory concentration ofapproximately 3 mM.

EXAMPLE 7 Effect of5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol (BST-4997) inRat Model of Diabetic Neuropathy

[0212] Our aim was to ascertain whether BST-4997 treatment could correctnerve dysfunction in streptozotocin (STZ)-diabetic rats. Animals (n=10)were made diabetic for 6 weeks (group D), following which they weretreated for 2 weeks with BST-4997 (group DBST) given in the drinkingwater at a concentration of 50 mg/L. They were compared to controlnon-diabetic rats (groups C). The data are presented in FIGS. 13-15.Statistical significance is reported according to the legend: **, ***p<0.01, p<0.001 versus untreated controls; ### p<0.001 treatment effectversus untreated diabetics.

[0213]FIG. 13 provides a graphical representation of the effect ofBST-4997 on restoring nerve conduction velocity (NCV) in the STZ rats.Motor NCV was tested between the sciatic notch and knee for the nervebranch to tibialis anterior muscle, as described in Cameron et al., Q.J. Exp. Physiol. 74: 917-926 (1989); and Cameron et al., Exp. Neurol.92: 757-761 (1986). Saphenous sensory NCV was measured between the groinand ankle.

[0214] These data clearly demonstrate that BST-4997 dramatically reducedthe diabetes-associated defect in both motor and sensory NCV in the STZrats.

[0215]FIG. 14 provides a graphical representation of the effect ofBST-4997 on restoring endoneurial perfusion in the STZ rats. Vascularblood flow, pressure, and conductance were measured. These data clearlydemonstrate that BST-4997 dramatically reduced the diabetes-associateddefects in endoneurial blood flow and conductance.

[0216]FIG. 15 provides a graphical representation of the effect ofBST-4997 on improving pain related measures in the STZ rats. Responsesto tactile allodynia, pressure, and thermal stimuli were measured. Thesedata clearly demonstrate that BST-4997 dramatically reduced thediabetes-associated defects in tactile allodynia and thermalhyperalgesia, as measured by latency for foot withdrawal from a noxiousheat stimulus.

[0217] Thus, these data clearly demonstrate that BST-4997 is effectivein correcting nerve dysfunction in a state of the art rat model ofdiabetic nephropathy.

EXAMPLE 8 Compound Binding to Plasma Albumin

[0218] This study was done to measure the binding of compounds of thepresent invention to plasma albumin. Such binding can result in longerplasma retention times and enhanced therapeutic efficacy for thecompounds. The proteins tested were bovine serum albumin, bovine (BSA)at 40 mg/ml and rat albumin at ˜13 mg/ml.

[0219] Spectrophotmetry: Two mL of protein solution in 0.1M phosphatebuffer saline (PBS) at pH 7.4 was titrated with compound in 0.2 Mphosphate buffer at pH 7.4. The protein concentration was prepared tohave absorbance less than 1 at the observation wavelength range(250-500), and the total volume change during titration was controlledbelow 2%. The compound-protein binding detection was based on the shiftof spectrum.

[0220] Free compound measurement: One ml of compound and protein mixturewas incubated at 37° C. for about 30 min and loaded into Centricon YM-10(10,000 MW cut-off, for BSA) or Microcon YC-3 (3,000 MW cut-off). Thesamples were centrifuged in a fixed-angle rotor at 6,000 rpm for about6-8 min (Centricon) or at 9,000 rpm for about 15 min (Microcon) to allowabout 10-20% of the volume to filter through. Free compound passesthrough the membrane while the free and complexed protein remains in thesample reservoir. The concentration of free compound in the filtrate isassumed to be the same as in the sample above the membrane. A fixedamount of filtrate aliquot was diluted to 0.6 ml with PBS at pH 7.4 (PBSwas prepared using 1 tablet from Sigma dissolved in 200 ml deionizedH₂O) and measured by UV absorbance. To quantify the percentage of freecompound, the same compound at the same concentration in PBS solution,as standard, was prepared in parallel through the same process, or acalibration curve was generated through the same process. 1 ml of PBSsolution (as blank) and 1 ml of protein solution (as control) also wentthrough the same process and measurement.

[0221] Calculations: The method used to determine the percentage of freecompound was either (a) % Freecompound=(A_(sample)−A_(control))/A_(standard)×100, where, A isabsorbance at selected wavelength; or (b) Obtaining free compoundconcentration of sample from calibration curve, and then divided bytotal concentration: K_(d)=[P][L]/[PL] (for 1:1 binding), using BSAMW=70,000.

[0222] Results: The results are provided in Tables 4-5 below, anddemonstrate that the compounds tested all bind to albumin, which mayprovide for enhanced plasma retention times and efficacy of thecompounds. TABLE 4 Results of BST4997 study Computed BST4997 % Free(1:1) Conc. Protein BST4997 K_(d) (mM) 10 μg/ml rat albumin˜13 mg/ml 67%0.35  5 μg/ml BSA 31% 0.26 40 mg/ml 10 μg/ml BSA 30% 0.24 40 mg/ml 20μg/ml BSA 38% 0.32 40 mg/ml

[0223] TABLE 5 Results of BST-4996 and BST-4944 studies % Free CompoundCompd. Conc. Protein Compound BST4996 8 μg/ml BSA 40 mg/ml 53% BST4944 8μg/ml BSA 40 mg/ml 34%

I claim:
 1. A compound of general formula I:

or pharmaceutically acceptable salts thereof, wherein L is N, N⁺O⁻, or N⁺-Z with any counterion, wherein Z is C₁-C₆ alkyl; A is a bond, C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkyl-O—, C₁-C₄ alkoxy C₁-C₄ alkyl-, —N(R₂₀)C₁-C₄ alkyl, —C₁-C₄ alkyl-N(R₂₀)—, —C₁-C₂ alkyl-N(R₂₀)—C₁-C₂ alkyl, —S—C₁-C₄ alkyl, —C₁-C₄ alkyl-S—, or C₁-C₄ thioalkoxy C₁-C₄ alkyl-, wherein R₂₀ is H or C₁-C₄ alkyl; R₈ is H, —CH₂OR₂ or OR₂; R₉ is —CH₂OR₁ or OR₁; R₁ and R₂ are independently H, C₁-C₆ alkyl, C₁-C₆ alkanoyl, C(O)NR₃R₄, C₁-C₆ alkoxy C₁-C₆ alkyl, arylalkyl or arylalkanoyl, wherein the alkyl, alkanoyl and alkoxy groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄ alkoxy or NH₂; R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, arylalkyl, arylalkanoyl, or —CO₂alkyl, —CO₂alkylaryl; wherein the aryl portion of each arylalkyl or each arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, 5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro; n is 0, 1, 2, or 3; R₇ and R₁₀ are independently H, C₁-C₆ alkyl or C₂-C₈ alkenyl, each of which is unsubstituted or substituted by 1 or 2 groups that are independently hydroxy, halogen, NR₃R₄, alkoxy, heteroarylalkoxy, heterocycloalkylalkoxy, arylalkoxy, or aryl; wherein 1 or 2 carbons of the alkyl or alkenyl group can be replaced with a C(O) group or a CHO group; Z is heterocycloalkyl or heteroaryl, which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, C₁-C₆ alkanoyl, hydroxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl NR₃R₄, wherein R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, arylalkyl, arylalkanoyl, —CO₂alkyl, or —CO₂ alkylaryl; each alkyl, alkoxy, and alkanoyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently hydroxy or halogen, the aryl, heteroaryl, and heterocycloalkyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro; any NH group in a heterocycloalkyl or heteroaryl group can optionally be NR₃, where R₃ is defined above; provided that the Z group is attached to the CH₂ group or the pyridine ring through a carbon-carbon bond; provided that when Z is tetrahydropyridine or piperidine, the Z group is attached via a carbon that is adjacent to a nitrogen atom.
 2. The compound of claim 1, wherein the Z group contains at least one nitrogen atom.
 3. The compound of claim 1 wherein A is C₁-C₄ alkyl, —O—C₁-C₄ alkyl, —C₁-C₄ alkyl-O—, C₁-C₄ alkoxy C₁-C₄ alkyl-, —N(R₂₀)C₁-C₄ alkyl, —C₁-C₄ alkyl-N(R₂₀)—, —C₁-C₂ alkyl-N(R₂₀)—C₁-C₂ alkyl, —S—C₁-C₄ alkyl, —C₁-C₄ alkyl-S—, or C₁-C₄ thioalkoxy C₁-C₄ alkyl-, wherein R₂₀ is H or C₁-C₄ alkyl; R₇ and R₁₀ are independently H, C₁-C₆ alkyl or C₂-C₈ alkenyl, each of which is unsubstituted or substituted by 1 or 2 groups that are independently hydroxy, NR₃R₄, heteroarylalkoxy, heterocycloalkylalkoxy, arylalkoxy, or aryl; wherein 1 or 2 carbons of the alkyl or alkenyl group can be replaced with a C(O) group or a CHO group; and Z is quinazoline; quinoxaline; imidazole; benzimidazole; piperazine; morpholine; thiomorpholine; quinoline; isoquinoline; 3-, 4-, 5-, 6-, 7-, or 8-tetrahydroisoquinoline; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrrole; pyrimidine; pyrazine; isothiazole; 4(3H)-pyrimidinone; isoxazole; 1,3,5-triazine; hexahydropyrimidine; furan; tetrahydrofuran; tetrahydropyrimidine; piperidine; tetrahydropyridine; indole; indoline; benzoxazole; 1H-1,2,3-triazole; azocine; or imidazolidine; each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, C₁-C₆ alkanoyl, hydroxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl NR₃R₄, wherein R₃ and R₄ at each occurrence areas defined above and each alkyl, alkoxy, and alkanoyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently hydroxy or halogen, the aryl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro, any NH group in a heterocycloalkyl or heteroaryl group can optionally be NR₃, where R₃ is defined above; provided that the Z group is attached to the CH₂ group through a carbon-carbon bond; provided that when Z is tetrahydropyridine or piperidine, the Z group is attached via a carbon that is adjacent to a nitrogen atom.
 4. The compound of claim 3 wherein Z contains at least two nitrogen atoms.
 5. The compound of claim 4 wherein R₇ and R₁₀ are independently H, C₁-C₆ alkyl, which is unsubstituted or substituted by 1 or 2 groups that are independently hydroxy, NR₃R₄, heteroarylalkoxy, heterocycloalkylalkoxy, arylalkoxy, or aryl; and Z is quinazoline; quinoxaline; imidazole; benzimidazole; piperazine; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrimidine; pyrazine; 4(3H)-pyrimidinone; 1,3,5-triazine; hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine; indole; indoline; 1H-1,2,3-triazole; or imidazolidine, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, alkanoyl, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl-NR₃R₄, wherein R₃ and R₄ at each occurrence are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, arylalkyl, arylalkanoyl, C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂alkylaryl each alkyl, alkoxy, and alkanoyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently hydroxy or halogen, the aryl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro, any NH group in a heterocycloalkyl or heteroaryl group can optionally be NR₃, where R₃ is defined above; and provided that the Z group is attached to the CH₂ group or the pyridine ring through a carbon-carbon bond.
 6. The compound of claim 5 wherein R₇ and R₁₀ are independently H, C₁-C₆ alkyl which is unsubstituted or substituted by 1 or 2 groups that are independently hydroxy, or NR₃R₄; wherein 1 or 2 carbons of the alkyl or alkenyl group can be replaced with a C(O) group or a CHO group; and Z is imidazole; benzimidazole; piperazine; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrimidine; pyrazine; hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine; indole; indoline; 1H-1,2,3-triazole; or imidazolidine, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl C₁-C₆ alkanoyl, phenyl C₁-C₆ alkoxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl-NR₃R₄, wherein R₃ and R₄ are independently H, C₁-C₆ alkyl, benzyl, benzoyl, C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂alkylphenyl; each alkyl, alkoxy, and alkanoyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently hydroxy, fluoro, or chloro; the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, fluoro, chloro, CF₃, OCF₃, or nitro; any NH group in a heterocycloalkyl or heteroaryl group can optionally be NR₃, where R₃ is defined above; provided that the Z group is attached to the CH₂ group through a carbon-carbon bond; provided that when Z is tetrahydropyridine or piperidine, the Z group is attached via a carbon that is adjacent to a nitrogen atom.
 7. The compound of claim 3 wherein the aryl portion of each arylalkyl or each arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro; and the alkyl, alkanoyl and alkoxy groups are independently substituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄ alkoxy or NH₂.
 8. The compound of claim 6 wherein R₁ and R₂ are independently hydrogen, C₁-C₄ alkyl, or benzyl; wherein the phenyl portion of each benzyl is unsubstituted or substituted with 1, 2, or 3, groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, fluoro, chloro, CF₃, OCF₃, or nitro; and wherein the alkyl groups are independently substituted with 1, or 2, groups that are independently hydroxy, methoxy, ethoxy, propoxy, isopropoxy or NH₂.
 9. The compound of claim 4 wherein R₇ and R₁₀ are independently H, C₁-C₆ alkyl, which is unsubstituted or substituted by 1 or 2 groups that are independently hydroxy, or NR₃R₄, heteroarylalkoxy, heterocycloalkylalkoxy, arylalkoxy, or aryl; and the aryl, heteroaryl, or heterocycloalkyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro,
 10. The compound of claim 1 wherein the compound is a compound of the formula:


11. The compound of claim 10 wherein the Z group contains at least one nitrogen atom.
 12. The compound of claim 11 wherein Z is quinazoline; quinoxaline; imidazole; benzimidazole; piperazine; morpholine; thiomorpholine; quinoline; isoquinoline; 3, 4, 5, 6, 7, or 8-tetrahydroisoquinoline; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrimidine; pyrazine; isothiazole; 4(3H)-pyrimidinone; isoxazole; 1,3,5-triazine; hexahydropyrimidine; furan; tetrahydrofuran; tetrahydropyrimidine; piperidine; tetrahydropyridine; indole; indoline, benzoxazole; 1H-1,2,3-triazole; azocine; or imidazolidine; each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo C₁-C₆ alkyl, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, alkanoyl, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl NR₃R₄, wherein R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, arylalkyl, arylalkanoyl, C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂alkylaryl; the aryl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro, provided that the Z group is attached to the pyridine ring through a carbon-carbon bond; and provided that when Z is hexahydropyrimidine, it is substituted with two or three groups.
 13. The compound of claim 12 wherein Z contains at least two nitrogen atoms.
 14. The compound of claim 13 wherein Z is quinazoline; quinoxaline; imidazole; benzimidazole; piperazine; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrimidine; pyrazine; 4(3H)-pyrimidinone; 1,3,5-triazine; hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine; indole; indoline; 1H-1,2,3-triazole; or imidazolidine, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, alkanoyl, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl-NR₃R₄.
 15. The compound of claim 14 wherein Z is imidazole; benzimidazole; piperazine; 1,2,4-triazole; hexahydropyridazine; tetrahydropyridazine; pyrazole; pyrimidine; pyrazine; hexahydropyrimidine; tetrahydropyrimidine; tetrahydropyridine; indole; indoline; 1H-1,2,3-triazole; or imidazolidine, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl C₁-C₆ alkanoyl, phenyl C₁-C₆ alkoxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl-NR₃R₄, wherein R₃ and R₄ are independently H, C₁-C₆ alkyl, benzyl, benzoyl, C₁-C₆ alkanoyl, —CO₂alkyl, —CO₂ alkylphenyl; each alkyl, alkoxy, and alkanoyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently hydroxy, fluoro, or chloro; and the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, fluoro, chloro, CF₃, OCF₃, or nitro.
 16. The compound of claim 15 wherein R₁ and R₂ are independently H, C₁-C₆ alkoxy C₁-C₆ alkyl, arylalkyl or arylalkanoyl, wherein and the alkyl, alkanoyl and alkoxy groups are independently substituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄ alkoxy or NH₂.
 17. The compound of claim 16 wherein R₁ and R₂ are independently hydrogen, C₁-C₄ alkyl, or benzyl, wherein the phenyl portion of each benzyl is unsubstituted or substituted with 1, 2, or 3, groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, fluoro, chloro, CF₃, OCF₃, or nitro; and the alkyl groups are independently substituted with 1, or 2, groups that are independently hydroxy, methoxy, ethoxy, propoxy, isopropoxy or NH₂.
 18. The compound of claim 1 wherein the compound is a compound of the formula:

or pharmaceutically acceptable salts thereof, and wherein R₈ is H, —CH₂OR₂ or OR₂; R₁ and R₂ are independently H, C₁-C₆ alkyl, C₁-C₆ alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, arylalkyl or arylalkanoyl, wherein the alkyl, alkanoyl and alkoxy groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently hydroxy, C₁-C₄ alkoxy or NH₂; R₃ and R₄ are independently H, C₁-C₆ alkyl, C₁-C₆ alkoxy, arylalkyl, arylalkanoyl, or —CO₂alkyl, —CO₂alkylaryl; wherein the aryl portion of each arylalkyl or each arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, 5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro; R₇ and R₁₀ are independently H, C₁-C₆ alkyl or C₂-C₈ alkenyl, each of which is unsubstituted or substituted by 1 or 2 groups that are independently hydroxy, halogen, NR₃R₄, alkoxy, heteroarylalkoxy, heterocycloalkylalkoxy, arylalkoxy, or aryl; wherein 1 or 2 carbons of the alkyl or alkenyl group can be replaced with a C(O) group or a CHO group; Z is heterocycloalkyl or heteroaryl containing 1, 2, or 3 nitrogen atoms, which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkoxy, halo, halo C₁-C₆ alkyl, aryl C₁-C₆ alkyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkoxy, C₁-C₆ alkanoyl, hydroxy, hydroxy C₁-C₆ alkyl, NR₃R₄, or —C₁-C₆ alkyl NR₃R₄, wherein R₃ and R₄ are as defined above; each alkyl, alkoxy, and alkanoyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently hydroxy or halogen, the aryl, heteroaryl, and heterocycloalkyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, haloalkyl, haloalkoxy, or nitro; any NH group in a heterocycloalkyl or heteroaryl group can optionally be NR₃, where R₃ is defined above.
 19. The compound of claim 18, wherein Z is heteroaryl.
 20. The compound of claim 19, wherein the heteroaryl is selected from the group consisting of pyridine, imidazole, diazole, and triazole.
 21. The compound of claim 18 wherein the Z group is attached to the pyridine ring through a carbon-carbon bond.
 22. The compound of claim 18 wherein Z contains 2 nitrogen atoms.
 23. The compound of claim 21 wherein Z contains an unsubstituted nitrogen atom on both sides of the attachment point of Z.
 24. The compound of claim 18 wherein the aryl substituents on Z are phenyl or phenyl derivatives.
 25. The compound of claim 1 selected from the group consisting of [2,4′]Bipyridinyl-3′-ol, 4-(1H-Imidazol-2-yl)-pyridin-3-ol, and 5-Hydroxymethyl-4-(1H-imidazol-2-yl)-2-methyl-pyridin-3-ol.
 26. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 27. A method for treating or inhibiting development of one or more AGE- and/or ALE-associated complications in subject in need thereof comprising administering one or more compounds according to claim 1 to the subject.
 28. A method for treating or inhibiting development of one or more AGE- and/or ALE-associated complications in a subject in need thereof comprising administering one or more pharmaceutical compositions according to claim 26 to the subject.
 29. The method of claim 27 wherein the one or more AGE- and/or ALE-associated complications are selected from the group consisting of accelerated protein aging, retinopathy, nephropathy, proteinuria, impaired glomerular clearance, neuropathy, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, atherosclerosis, cardiovascular disease, neurodegenerative amyloid diseases, diabetes-associated hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, urinary stone disease, obesity-related complications, proliferation of smooth muscle cells in the aorta, coronary artery occlusion, hypertension; and dialysis-related disorders selected from the group consisting of dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increases in permeability of the peritoneal membrane in a dialysis patient, renal failure progression in a dialysis patient, and ultrafiltration failure and peritoneal membrane destruction in a dialysis patient.
 30. A method for treating or inhibiting development of one or more disorders selected from the group consisting of diabetic nephropathy, proteinuria, impaired glomerular clearance, retinopathy, neuropathy, atherosclerosis, diabetes-associated hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, urinary stone disease, obesity-related complications proliferation or smooth muscle cells in the aorta, coronary artery occlusion, and hypertension; and dialysis-related disorders including dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increases in permeability of the peritoneal membrane in a dialysis patient, renal failure progression in a dialysis patient, and inhibiting ultrafiltration failure and peritoneal membrane destruction in a dialysis patient, wherein the method comprises administering an effective amount of a compound according to claim 1 to a subject in need of such treatment.
 31. A method for treating or inhibiting development of one or more disorders selected from the group consisting of diabetic nephropathy, proteinuria, impaired glomerular clearance, retinopathy, neuropathy, atherosclerosis, diabetes-associated hyperlipidemia, oxidative modification of proteins, arthritis, connective tissue diseases, amyloidosis, urinary stone disease, obesity-related complications proliferation or smooth muscle cells in the aorta, coronary artery occlusion, and hypertension; and dialysis-related disorders including dialysis-related cardiac morbidity and mortality, dialysis-related amyloidosis, dialysis-related increases in permeability of the peritoneal membrane in a dialysis patient, renal failure progression in a dialysis patient, and inhibiting ultrafiltration failure and peritoneal membrane destruction in a dialysis patient, wherein the method comprises administering an effective amount of a pharmaceutical composition according to claim 26 to a subject in need of such treatment. 